1. Field of the Invention
The present invention relates to certain thiazolidinone derivatives useful as modulators of the chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-1, CXCR-2, CXCR-3, and/or CXCR-4 and to pharmaceutical compositions that include these compounds and a pharmaceutically acceptable carrier. In addition, the present invention is directed to methods for inhibiting HIV infectivity.
2. Summary of the Related Art
Chemokines mediate a range of proinflammatory effects on leukocytes, such as chemotaxis, degranulation, and intigran activation (Baggiolini et al., Adv. Immunol., 1994;55:97-179; Oppenheim et al., Annu. Rev. Immunol., 1991; 9:617-648; Miller et al., Crit. Rev. Immunol., 1992;12:17-46). These effects are mediated by binding to the seven-transmembrane-spanning G-protein coupled receptors (Baggiolini et al., Adv. Immunol., 1994;55:97-179; Murphy, Annu. Rev. Immunol., 1994;12:593-633; Schall et al., Curr. Opin. Immunol., 1994;6:865-873; Gerard et al., Curr. Opin. Immunol., 1994;6;140-145; Mackay, Curr. Bio., In press). Chemokine receptors also serve as co-receptors for HIV-1 entry into cells. This came from observations that RANTES, MIP-1xcex1, and MIP-1xcex2 suppressed infection of susceptible cells in vitro by macrophage-tropic primary HIV-1 isolates (Cocchi et al., Science (Wash. D.C.), 1995;270:1811-1815). The chemokine receptor CXCR-4 is found to support infection and cell fusion of CD4+ cells by laboratory-adapted, T-tropic HIV-1 strains (Feng et al., Science (Wash. D.C.), 1996;272:872-877). CCR-5, a RANTES, MIP-1xcex1, and MIP-1xcex2 receptor, is subsequently identified as the principle co-receptor for primary macrophage-tropic strains (Choe et al., Cell, 1996;85:1135-1148; Alkhatib et al., Science (Wash. D.C.), 1996;272:1955-1958; Doranz et al., Cell, 1996;85:1149-1158; Deng et al., Nature (Lond.) 1996;381:661-666; Dragic et al., Nature (Lond.), 1996;381:667-3). The importance of CCR-5 for HIV-1 transmission is underscored by the observation that certain individuals who had been repeatedly exposed to HIV-1 but remained uninfected had a defect in CCR-5 expression (Liu et al., Cell, 1996; 86:367-377; Samson et al., Nature (Lond.), 1996;382:722-725; Dean et al., Science (Wash. D.C.), 1996;273:1856-1862; Huang et al., Nature Med., 1996;2:1240-1243). These noninfectable individuals are found to be homozygous for a defective CCR-5 allele that contains an internal 32-base pair deletion (CCR-5 xcex9432). The truncated protein encoded by this gene is apparently not expressed at the cell surface. CCR-5 xcex9432 homozygous individuals comprise xcx9c1% of the Caucasian population and heterozygous individuals comprise xcx9c20%. In studies of about 2700 HIV-1 infected individuals, no xcex9432 homozygotes are found. Individuals who are heterozygous for xcex9432 CCR-5 allele have been shown to progress more slowly to AIDS than wild-type homozygous individuals (Samson et al., Nature (Lond.), 1996;382:722-725; Dean et al., Science (Wash. D.C.), 1996;273:1856-1862; Huang et al., Nature Med., 1996;2:1240-1243). Thus, the identity of CCR-5 as the principle co-receptor for primary HIV isolates provides an opportunity to understand disease pathogenesis, and more importantly to identify a new avenue for the treatment of HIV-1 infection.
The instant invention is a series of finctionalized heterocycles that block the CD-4/GP-120 interaction with CCR-5 receptor, and thus can be useful in the treatment of HIV infection manifested in AIDS.
The compounds of the invention are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation, the method comprising the administration of an effective amount of the compound to a subject, preferably mammalian, in need thereof.
The present invention is directed to the use of thiazolidinone derivatives as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of chemokine receptors, including CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, CXCR1, CXCR2, and/or CXCR-4. In particular, the compounds of the present invention are preferred as modulators of the chemokine receptor CCR-5.
The compounds of the invention are those having the structure of Formula 1: 
R1 and R2 are independently hydrogen, lower alkyl, halogen, hydroxy, or lower alkoxy; or
aryl, arylalkyl, heteroaryl, or heteroarylalkyl where each ring is optionally substituted independently with up to three groups selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, nitro, trifluoromethyl, amino, mono- or dialkylamino, carbamoyl, carboxyalkyl, alkoxycarbonylalkyl, sulfamoyl, or carbonylamino, provided R1 and R2 are not both hydroxy or lower alkoxy;
R3 and R4 independently represent hydrogen, lower alkyl, cycloalkyl, aminoalkyl, or mono- or dialkylaminoalkyl; or
aryl or heteroaryl optionally substituted with up to three groups selected from halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, nitro, trifluoromethyl, amino, mono- or dialkylamino, carbamoyl, carboxyalkyl, alkoxycarbonylalkyl, sulfamoyl, or carbonylamino;
R5 represents a carbocyclic group containing from 3-7 members, up to two of which members are optionally heteroatoms selected from oxygen and nitrogen, where the carbocyclic group is optionally substituted with one or two groups selected from halogen, lower alkyl, lower alkoxy, mono- or dialkylamino, aryl, arylalkyl, or a heterocyclic group; or
R5 is (CR6R7)xe2x80x94(CH2)nxe2x80x94XR8R9;
X is S or N;
R6 and R7 independently represent hydrogen, lower alkyl, hydroxy, amino, or mono- or dialkylamino;
n is 0, 1, 2, 3, or 4; and
R8 and R9 independently represent hydrogen, lower alkyl, lower alkenyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, or cycloalkyl; or
R8 and R9 together with the nitrogen to which they are attached form a heterocyclic ring containing from 5-7 members, up to two of which members are optionally heteroatoms selected from oxygen, sulfur, and nitrogen, where the heterocyclic group is optionally substituted with one or two groups selected from halogen, lower alkyl, lower alkoxy, mono- or dialkylamino, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, or heterocyclic group.
Preferred compounds have Formula Ia 
wherein R22 and R33 independently are hydrogen, halo, alkyl, and trihaloalkyl, and R5 is as defined above. Especially preferred are such compounds wherein R5 is alkyl such as propyl, substituted with a heterocyclic group such as piperidyl, piperazinyl, or morpholinyl, and where such heterocyclic group is unsubstituted or substituted with a cyclic or heterocyclic group such as cyclohexyl, pyridinyl, morpholino, piperidinyl, or pyrinidyl.
Another preferred set of compounds have Formula Ib 
wherein R3 and R4 together form a heteroaryl ring such as pyridyl, pyrrolyl, and thienyl, R22 is hydrogen, halo, alkyl, and haloalkyl, and R5 is as defined above, and especially substituted alkyl.
The instant invention includes pharmaceutical compositions of compounds of Formula I and methods of using the compounds for modulating chemokine receptor activity, preventing or treating infection by HIV, delaying the onset of AIDS, treating AIDS, and treating inflammatory disease.
The novel compounds encompassed by the instant invention are those described by the general Formula I set forth above, and the pharmaceutically acceptable salts, esters, amides, and prodrugs thereof.
Preferred compounds of Formula I are those in which R4 is hydrogen; R3 is dialkylaminoalkyl or aryl, heteroaryl, or cycloalkyl optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino; A is S; and R1 is hydrogen; R2 is aryl or heteroaryl optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino.
In addition to the compounds of Formula I, the invention encompasses compounds of Formula II: 
wherein
R3, R4, R5, and A are as defined above for Formula I;
R11 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, nitro, trifluoromethyl, amino, mono- or dialkylamino, carbamoyl, carboxyalkyl, alkoxycarbonylalkyl, sulfamoyl, or carbonylamino; and
B, C, D, and E independently represent CH or N, provided that no more than two of B, C, D, and E are N.
Preferred compounds of Formula II are those in which all of B, C, D, and E are CH or only one of B, C, D, and E is nitrogen; R4 is hydrogen; R3 is dialkylaminoalkyl, or aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino; and R11 is hydrogen or halogen.
In addition, the invention encompasses compounds of Formula III: 
wherein R1, R2, R5, and A are as defined above for Formula I and Rxe2x80x2 is as defined above for R11 in Formula II.
Preferred compounds of Formula III are those in which R11 is hydrogen; A is S; R2 is dialkylaminoalkyl, or aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino; and R11 is hydrogen or halogen.
In addition, the invention encompasses compounds of Formula IV: 
wherein
R1, R2, R5, and A are as defined above for Formula I; and
R12 is cycloalkyl or heteroaryl, each of which is optionally substituted with halogen, lower alkyl, lower alkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, nitro, trifluoromethyl, amino, mono- or dialkylamino, carbamoyl, carboxyalkyl, alkoxycarbonylalkyl, sulfamoyl, or carbonylamino.
Preferred compounds of Formula IV are those in which R12 is cyclohexyl, 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, or 2- or 3-quinolinyl, each of which is optionally substituted with halogen or lower alkyl; R1 is hydrogen; A is S; and R2 is dialkylaminoalkyl, or aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted with halogen, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino.
In addition, the invention encompasses compounds of Formula V: 
wherein
R1, R2, R3, R4, and A are as defined above for Formula I;
m is 0, 1, 2, or 3; and
R14 and R15 independently represent hydrogen, lower alkyl, lower alkenyl, or cycloalkyl; or
R14 and R15 together with the nitrogen to which they are attached form a heterocyclic ring containing from 5-7 members, up to two of which members are optionally heteroatoms selected from oxygen, sulfur, and nitrogen, where the heterocyclic group is optionally substituted with one or two groups selected from halogen, lower alkyl, lower alkoxy, mono- or dialkylamino, aryl, arylalkyl, or a heterocyclic group.
Preferred compounds of Formula V are those in which m is 2; and R14 and R15 independently represent hydrogen or lower alkyl, or R14 and R15 together with the nitrogen to which they are attached form a morpholine ring or a piperidine ring, each of which is optionally substituted with a heterocycle, aryl, or arylalkyl.
The terms xe2x80x9calkyl,xe2x80x9d xe2x80x9clower alkyl,xe2x80x9d or xe2x80x9c(C1-C6)-alkylxe2x80x9d mean a straight or branched hydrocarbon having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also be substituted with one or more of the substituents listed below for aryl.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring which contains from 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
By xe2x80x9calkoxy,xe2x80x9d xe2x80x9clower alkoxy,xe2x80x9d or xe2x80x9c(C1-C6)-alkoxyxe2x80x9d in the present invention is meant straight or branched chain alkoxy groups having 1 to 6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
The term xe2x80x9carylxe2x80x9d means an unsubstituted aromatic carbocyclic group having a single ring (eg, phenyl), multiple rings (eg, biphenyl), or multiple condensed rings in which at least one is aromatic (eg, 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), unsubstituted or substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, xe2x80x94CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, xe2x80x94(CH2)mCO2H, xe2x80x94(CH2)mCO2-alkyl, xe2x80x94(CH2)mSO3H, xe2x80x94NH alkyl, xe2x80x94N(alkyl)2, xe2x80x94(CH2)mPO3H2, xe2x80x94(CH2)mPO3(alkyl)2, xe2x80x94(CH2)mSO2NH2, and xe2x80x94(CH2)mSO2NH-alkyl wherein alkyl is defined as above and m is 0, 1, 2, or 3.
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d means an alkyl moiety (as defined above) substituted with an aryl moiety (also as defined above).
By halogen in the present invention is meant fluorine, bromine, chlorine, and iodine, and their monovalent radicals.
By heteroaryl (aromatic heterocycle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl. The term xe2x80x9csubstituted heterocyclexe2x80x9d means a heterocycle substituted by 1 to 3 substituents selected from alkyl, O-alkyl and S-alkyl, OH, SH, xe2x80x94CN, halogen, 1,3-dioxolanyl, CF3, NO2, NH2, NHCH3, N(CH3)2, NHCO-alkyl, xe2x80x94(CH2)mCO2H, xe2x80x94(CH2)mCO2-alkyl, xe2x80x94(CH2)mSO3H, xe2x80x94NH-alkyl, xe2x80x94N(alkyl)2, xe2x80x94(CH2)mPO3H2, xe2x80x94(CH2)mPO3(alkyl)2, xe2x80x94(CH2)mSO2NH2, and xe2x80x94(CH2)mSO2NH-alkyl wherein alkyl is defined as above and m is 0, 1, 2, or 3.
The term xe2x80x9cheteroalkylxe2x80x9d means an alkyl moiety (as defined above) substituted with a heteroaryl moiety (also as defined above).
Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma. Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge supra., 1977).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
Representative compounds of the invention are shown below in Table 1, below. Each compound is assigned a number, which number will be referred to below in the working examples and in subsequent tables.
Representative compounds of the present invention, which are encompassed by Formula I include, but are not limited to, the compounds in Table 1 and their pharmaceutically acceptable acid or base addition salts, or amide or prodrugs thereof, as well as solvates and hydrates thereof.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula 1.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of HIV infection, the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
The compounds of Formula I are valuable antagonists of the CCR-5 chemokine receptor. As such, these compounds are useful scientific research tools for studying the role of CCR-5 in various biological processes in vitro. Compounds which are antagonists of the CCR-5 chemokine receptor are expected to have efficacy in inhibiting HIV infection and are thus useful in the treatment of AIDS. The compounds of the present invention are evaluated in a CCR-5 receptor binding assay (see below).
The examples presented below are intended to illustrate particular embodiments of the invention, and are not intended to limit the scope of the specification or the claims in any way.
An illustration of the preparation of compounds of the present invention is shown in Schemes 1-2. R1, R11, R8, and R9 are as defined above for Formula I.
Armed with the disclosure provided herein (particularly the schemes and the synthetic examples that follow) and knowledge common to all who practice in the field, those of ordinary skill in the art will be able to make and use the entire scope of compounds disclosed herein.
The invention compounds can be prepared by any of several synthetic methods, utilizing standard methodologies well-known to those skilled in organic chemistry. Preferred methods of synthesis of the final target compounds is shown in Schemes 1-2.
In Scheme 1, a Schiff base is first prepared from the corresponding aryl aldehyde and a haloalkylamine, for example, 3-chloropropylamine. The imine intermediate (Schiff base) is then reacted with a cyclizing agent such as mercaptoacetic acid to afford a substituted 4-thiazolidinone. The chloride is displaced with an amine in the presence of base, preferably a tertiary base, to afford the 3-aminosubstitutedpropyl-4-thiazolidinone. This thiazolidinone is reacted with an aryl aldehyde such as benzaldehyde in the presence of a strong base, as, for example, potassium t-butoxide, to yield the 5-methylene thiazolidinone of the invention. 
Alternatively, the synthetic sequence depicted in Scheme 2 can be used to prepare the compounds of the invention. For example, a benzaldehyde is reacted with a 3-aminosubstituted propylamine to afford a Schiff base. As in Scheme 1, the imine Schiff base intermediate is next reacted with mercaptoacetic acid at reflux to afford the corresponding 4-thiazolidinone. The 4-thiazolidinone is subsequently reacted with another benzaldehyde in the presence of a strong base, as, for example, potassium t-butoxide to yield the final product. The route shown in Scheme 2 is especially suited for preparing invention compounds having a second substituent at the 2-position of the 4-thiazolidinone. 
The present invention is further directed to combinations of the present compounds with one or more agents useful in the prevention or treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or postexposure, in combination with effective amounts of the anti-HIV compounds, immunomodulators, anti-infectives, or prophactic or therapeutic vaccines known to those of ordinary skill in the art. Examples of such compounds are found in Table 2, below.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
The invention is illustrated further by the following detailed examples. The examples are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.
The starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods.